Thiamine deficiency induced pathologic damage in humans is associated with Wernicke-Korsakoff's disease, mixed sensor motor neuropathy and infantile subacute necrotizing encephalopathy. The prevalence of Wernicke-Korsakoff pathologic changes ranges from l.7-2.8% among all autopsies to as high as 12.5% among chronic alcoholics. Individuals with Wernicke-Korsakoff disease suffer from anterograde and retrograde amnesia, cognitive dysfunctions, multimodal sensor discrimination deficits, and emotional flattening and thus require constant care and institutionalization. An important feature of these thiamine deficiency disorders is the selective vulnerability of specific brain regions to pathologic damage. Regions of thalamus, mammillary bodies, and certain brainstem nuclei are consistently damaged in Wernicke-Korsakoff's disease and are probably responsible for the behavioral deficits. Despite this knowledge, the biochemical and physiological mechanisms responsible for the lesions and their topographic distribution in the brain following acute thiamine deficiency remain unknown. Consequently, there is currently no therapeutic treatment for the abrupt cessation of ongoing pathologic events during acute thiamine deficiency. The long-term objective of this project is to develop effective treatments for the prevention of brain lesions and associated cognitive and memory deficits produced by thiamine deficiency. Important goals are to understand the bases for regional vulnerability of brain structures to impaired energy metabolism and to explore the utility of the pyrithiamine- induced thiamine deficiency (PTD) rat as a model for studying vascular edematous necrosis in the brain. The immediate goal of this project is to test the hypothesis that release of histamine is critical to the development of glutamate-NMDA receptor mediated excitotoxic lesions within thalamus. The specific goals are to conduct the following studies in the PTD rat model of Wernicke-Korsakoff's disease: (l) using in vivo microdialysis, measure the temporal course of histamine release within vulnerable (thalamus) and unaffected (hippocampus) regions of the brain prior to and during onset of lesions; (2) determine if inhibition of histamine release prevents rise in ECF glutamate and/or protects against lesions; (3) determine if direct infusion of histamine produces either immediate or delayed neurotoxic changes in thalamus and hippocampus of PTD and controls. (4) determine if antagonism of NMDA receptors with MK-801 prevents pathologic changes produced by direct infusion of histamine; and (5) determine if antagonism of H1 and H2 histamine receptors attenuates PTD-induced pathologic damage and the rise in extracellular glutamate in vulnerable regions of thalamus.